Cancer is a generic term for a large group of diseases that can affect any part of the body. One defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs, the latter process is referred to as metastasizing. Metastases are the major cause of death from cancer.
Cancers figure among the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer related deaths in 2012. The most common causes of cancer death are cancers of lung (1.59 million deaths), liver (745 000 deaths), stomach (723 000 deaths), colorectal (694 000 deaths), breast (521 000 deaths), esophageal cancer (400 000 deaths). Among men, the 5 most common sites of cancer diagnosed in 2012 were lung, prostate, colorectal, stomach, and liver cancer. Among women the 5 most common sites diagnosed were breast, colorectal, lung, cervix, and stomach cancer.
The number of new cases is expected to rise by about 70% over the next two decades (World Cancer Report 2014, WHO).
Despite extraordinary advances in our understanding of the biology that underlies the development and progression of cancer as well as potential molecular targets for its treatment, more than 90% of all new oncology drugs that enter clinical development do not obtain marketing approval. Many drugs fail in late stages of development—often in Phase III trials—because of inadequate activity, lack of strategies for combating resistance to these drugs, unexpected safety issues or difficulties in determining efficacy because of reasons that include confounded outcomes of clinical trials. Moreover, an increased understanding of cancer biology has shown that cancers are heterogeneous diseases, which suggests that there is a high likelihood that effective cancer treatments will need to address patient-specific molecular defects and aspects of the tumor microenvironment.
The widespread occurrence of cancer and the high degree of heterogeneity of this disease underscores the need for improved anticancer regimens for the treatment of malignancy. The recent use of large panel of cancer cell lines agents is becoming an important tool for the discovery and evaluation of potential new anti-cancer. Indeed, large panel of tumor-derived cell lines may recapitulate the genotype-response relationship of new therapeutic agents and may be of utmost interest.
The present invention provides new compounds of formula (I) for the treatment of diseases related to cell proliferation, such as hematopoietic cancers or solid cancers.
Compounds of the invention have an anti-tumoral activity on a very large panel of cancer cell lines.
Compounds of formula (I) comprise a 6-membered aryl or heteroaryl moiety para-substituted by A and B moieties. Compounds comprising a 6-membered aryl or heteroaryl moiety meta-substituted by heteroaryl and heterocycle groups are disclosed in WO2013/014170. Compounds of WO2013/014170 are tyrosine kinases inhibitors and may be used for the treatment of proliferative diseases. Surprisingly, compounds of formula (I) the invention are not tyrosine kinase inhibitors, while having anti-proliferative properties. Therefore, compounds of the invention offer a new route of treatment of diseases related to cell proliferation.